Two frequent uses of fluoxetine are called into question by the results of new studies Reported in this month’s American Journal of Psychiatry.

One study, a 10-week, double-blind trial, showed that fluoxetine is no more effective than imipramine in the acute treatment of atypical depression. The finding contradicts earlier studies demonstrating that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, were more effective than tricyclic antidepressants. Neither drug achieved a treatment response comparable with that found in earlier studies with monoamine oxidase inhibitors (MAOIs).

SSRIs may still be considered the treatment of choice, however, because patients tolerate this class of drug better than either tricyclic antidepressants or MAOIs. In the new study patients were more likely to continue taking fluoxetine than imipramine. The side effects and dietary restrictions associated with the use of MAOIs have been shown in past work to reduce compliance, especially during the continuation and maintenance treatment.

In the new study, Patrick J. McGrath, M.D., and his colleagues at Columbia University, randomly assigned 154 subjects to one of three groups receiving fluoxetine, imipramine, or placebo. The mean daily dose of fluoxetine was 51.4 mg and of imipramine was 204.9 mg.

Response to both active medications was significantly better than to placebo. Among those who completed the study, 57 percent responded to fluoxetine, and 74 percent responded to imipramine. Only 14 percent of the subjects who received fluoxetine dropped out of the study, whereas 34 percent of those who received imipramine and 23 percent of those who received a placebo dropped out. This difference would tend to inflate the response rate for imipramine. The authors concluded that neither drug was superior to the other.

McGrath and his colleagues recommend that SSRIs should be the first choice in treating atypical depression and MAOIs reserved for nonresponders. They point out that the degree of functional improvement seen among responders in their recent study suggests that the superiority of MAOIs demonstrated in other studies is not in the degree of improvement but rather in the probability of achieving a response.

The trial comparing fluoxetine and imipramine in atypical depression was an indirect attempt to test the efficacy of the newer drug against MAOIs. Differences in method made it impossible for the New York investigators to determine the relative efficacy of fluoxetine and MAOI by comparing the results of the new study with those of older trials of imipramine versus MAOI. Safety and compliance considerations make it unlikely that a large-scale clinical trial directly comparing an SSRI and an MAOI will be done. McGrath and his colleagues suggest that the efficacy of heterocyclic antidepressants other than the SSRIs should be studied further in patients with atypical depression.

The Columbia University investigative team was largely responsible for defining and validating the atypical subtype of depression. Atypical depression is marked by emotional reactivity, especially pathological sensitivity to interpersonal rejection, and severe lack of physical energy. Other symptoms not associated with most other forms of depression, such as overeating and oversleeping, are also common.

The response to MAOIs is one of several types of evidence that support the distinctiveness of the disorder. Estimates of the prevalence of atypical depression vary considerably, but the disorder is thought to affect a third to nearly a half of depressed outpatients.

In another placebo-controlled, double-blind study reported in the same issue, nortriptyline produced a significantly higher antidepressant response rate than fluoxetine or placebo in patients with poststroke depression. Nortriptyline also proved superior in improving symptoms of anxiety and helping patients return to activities of daily living. Neither drug affected recovery of cognitive and social functioning.

The study was conducted by Robert G. Robinson and his colleagues at the University of Iowa, along with researchers from the Raul Carrea Institute of Neurological Research in Buenos Aires, Argentina.

Of the 104 stroke patients in the study, 56 were diagnosed with depression. The 48 nondepressed patients were included to determine whether improvement was related to recovery from depression or to an unrelated neurochemical effect. Those who were randomly assigned to the nortriptyline group received doses of 25 mg a day that was gradually increased to 100 mg. The fluoxetine group received doses of 10 mg a day, gradually increased to 40 mg. Both active-medication groups and the placebo group were treated over 12 weeks.

Unlike patients treated with nortriptyline, those who received the SSRI lost a significant amount of weight. Because the patients were elderly, this side effect was cause for concern. Nine of the 23 fluoxetine patients dropped out of the study, compared with three of the 15 treated with nortriptyline. Robinson and his associates speculate that significant side effects may have contributed to the high dropout rate in the fluoxetine group.

The investigators were surprised by one finding in the study. Neither the depressed nor the nondepressed patients treated with either medication showed significantly greater improvement in stroke-associated impairments than those who received placebo. Because past research has shown such improvement, Robinson and his colleagues suggest that future research should identify specific subgroups of patients, alternative measurement scales, or optimal time to begin and maintain treatment.